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. 2015 Nov 20;10(11):e0143316.
doi: 10.1371/journal.pone.0143316. eCollection 2015.

Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation

Daichi Maeda  1   2 , Yoshiyuki Akiyama  3   4 , Teppei Morikawa  1 , Akiko Kunita  1 , Yasunori Ota  5 , Hiroto Katoh  6 , Aya Niimi  3 , Akira Nomiya  3 , Shumpei Ishikawa  6 , Akiteru Goto  2 , Yasuhiko Igawa  4 , Masashi Fukayama  1 , Yukio Homma  3
Affiliations

Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation

Daichi Maeda et al. PLoS One. .

Abstract

Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P <0.0001). Substantial lymphoplasmacytic inflammation (≥200 cells/mm2) was observed in 93% of HIC specimens, whereas only 8% of NHIC specimens were inflamed. Plasmacytic infiltration was more prominent in HIC specimens compared with NHIC and non-IC cystitis specimens (P <0.005). Furthermore, expansion of light-chain-restricted B-cells was observed in 31% of cases of HIC. The amount of residual epithelium was decreased in HIC specimens compared with NHIC specimens and non-IC cystitis specimens (P <0.0001). These results suggest that NHIC and HIC are distinct pathological entities, with the latter characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. An abnormality in the B-cell population may be involved in the pathogenesis of HIC.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Digital image analysis.
(A) Quantification of CD3-positive cells. CD3 immunostaining (left) and identification of CD3-positive cells by image analysis software (right). (B) Evaluation of epithelium/specimen ratio. Measurement of specimen area, circled in orange (left), and identification and measurement of cytokeratin-positive area (right).
Fig 2
Fig 2. Representative histology of non-Hunner-type interstitial cystitis (NHIC) biopsy specimen.
(A) low-power view reveals unremarkable bladder mucosa; (B) overlying epithelium is well preserved; no stromal inflammation is seen; (C) lymphocytes are only occasionally found in the lamina propria. (D–F) Representative histology of the HIC biopsy specimen taken from background (non-Hunner lesion) mucosa (HIC-BG): (D) diffuse inflammatory cell infiltration with focal aggregate of lymphocytes present in the subepithelial layer; (E) dense subepithelial inflammation observed in a linear pattern; (F) inflammatory cells predominantly composed of lymphocytes and plasma cells; epithelium is irregularly denuded. (G–I) Representative histology of the Hunner lesions of patients with HIC: (G) low-power view; (H) subepithelial layer diffusely inflamed; (I) epithelium completely denuded and numerous plasma cells found in the underlying stroma.
Fig 3
Fig 3. Evaluation of inflammatory cell infiltration and residual epithelium by image analysis software.
(A) Lymphoplasmacytic infiltration in non-Hunner-type interstitial cystitis (NHIC), HIC-BG (background mucosa), HIC-HL (Hunner lesion) and non-IC cystitis specimens. Lateral bars indicate the means. Lymphoplasmacytic infiltration was much more severe in HIC-BG and HIC-HL than NHIC. The number of infiltrating mononuclear cells in NHIC specimens was very few (<200 cells/mm2) in most cases. The non-IC cystitis group showed a similar degree of mononuclear cell inflammation to that of HIC-BG and HIC-HL. (B) Plasma cell ratio in NHIC, HIC-BG, HIC-HL and non-IC cystitis specimens. This was significantly higher in HIC-HL and HIC-BG than in NHIC and non-IC cystitis. (C) Epithelium/specimen ratio in NHIC, HIC-BG, HIC-HL and non-IC cystitis specimens. Lateral bars indicate the means. The epithelium/specimen ratio is significantly lower in HIC specimens compared with NHIC and non-IC cystitis specimens (P <0.0001).
Fig 4
Fig 4. Inflammation and epithelial denudation in HIC cases.
(A) Each case of Hunner-type/classic IC (HIC) was plotted for lymphoplasmacytic infiltration in Hunner lesion (HIC-HL) and background mucosa (HIC-BG) (n = 27). There was no significant correlation between the degree of inflammation in HIC-HL and that in HIC-BG. In 18 of 27 cases, lymphoplasmacytic infiltration was denser in HLs than in the BG. (B) Each case of HIC was plotted for the epithelium/specimen ratio of HIC-HL and HIC-BG (n = 27). There was no significant correlation between the degree of epithelial loss in HIC-HL and that in HIC-BG. In 19 of 27 cases, the epithelium/specimen ratio was lower in HLs than in the BG.
Fig 5
Fig 5. Correlation between lymphoplasmacytic infiltration and epithelium/specimen ratio in Hunner-type/classic IC specimens.
Degree of lymphoplasmacytic infiltration did not correlate with the amount of residual epithelium.
Fig 6
Fig 6. Hunner-type/classic IC (HIC) specimen with expansion of light chain-restricted B cells (κ >>> λ).
(A) A dense plasmacytic infiltration is observed in the subepithelial stroma. (B) In situ hybridization for the κ chain reveals numerous κ-positive cells. (C) In situ hybridization for the λ chain reveals only a few λ-positive cells.
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References

    1. van de Merwe JP. Interstitial cystitis and systemic autoimmune diseases. Nat Clin Pract Urol. 2007;4(9):484–91. - PubMed
    1. Keller JJ, Liu SP, Lin HC. A case-control study on the association between rheumatoid arthritis and bladder pain syndrome/interstitial cystitis. Neurourol Urodyn. 2013;32(7):980–5. 10.1002/nau.22348 - DOI - PubMed
    1. Peeker R, Fall M. Toward a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease. J Urol. 2002;167(6):2470–2. - PubMed
    1. Fall M, Aldenborg F, Johansson S, Peeker R. Clinical characteristics support that interstitial cystitis is a heterogeneous syndrome. Urology. 2001;57(6 Suppl 1):129–30. - PubMed
    1. Harrington DS, Fall M, Johansson SL. Interstitial cystitis: bladder mucosa lymphocyte immunophenotyping and peripheral blood flow cytometry analysis. J Urol. 1990;144(4):868–71. - PubMed

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This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI) (YH), ‘Basic Science and Platform Technology Program for Innovative Biological Medicine’ (SI) from the Ministry of Education, Science, Sports and Culture, and Mitsui Life Social Welfare Foundation (DM).